The present invention relates to a process for preparing [bis-(trifluoromethyl)-phenyl]-acetic acids and alkyl esters thereof from bromo-bis-(trifluoromethyl)- benzenes and dialkyl malonates and to dialkyl [bis-(trifluoromethyl)-phenyl]-malonates which can be obtained as intermediates in this process.
Bis-(trifluoromethyl)-substituted phenylacetic acids and derivatives thereof are important intermediates for pharmaceutically active compounds (see, for example, U.S. Pat. No. 5,817,658, WO 98/00405, WO 98/07722, WO 95/21819 and U.S. Pat. No. 5,696,267).
WO 96/05827 describes the preparation of 2,4-bis-(trifluoromethyl)-phenylacetic acid by acid hydrolysis of the corresponding phenylacetonitrile. The yield of 68.5% is unsatisfactory. The nitrile was prepared from 2,4-bis(-trifluoromethyl)-benzyl bromide, which is difficult to obtain, by reaction with a large excess of sodium cyanide. Owing to its toxicity, the handling and disposal of the sodium cyanide requires considerable expense with respect to industrial hygiene.
Methyl 3,5-bis(trifluoromethyl)-phenylacetate can be prepared by esterification of the corresponding acid with thionyl chloride in the presence of methanol (WO 95/21819). No details are given here with respect to the synthesis of the bis-(trifluoromethyl)-phenylacetic acid structure.
The same ester can also be obtained in a yield of about 75% of theory by base hydrolysis and acid work-up from 1-xcex2,xcex2,xcex2-trichloroethyl-3,5-bis-(trifluoromethyl)-benzene. This, in turn, was obtained by reaction of 3,5-bis-(trifluoromethyl)-aniline, which has been diazotized in hydrochloric acid, with vinylidene chloride in a yield of 73% (DE 33 14 249). It is generally known that the yields in this type of reaction are not reproducible and vary considerably. When this process was repeated, yields of barely 10 to barely 50% of theory were achieved. In addition, vinylidene chloride (1,1-dichloroethene) is a carcinogenic substance which can only be handled with considerable expense.
Accordingly, there continues to be a demand for a simple process for preparing [bis-(trifluoromethyl)-phenyl]-acetic acids and alkyl esters thereof in high yields requiring the handling of less toxic and noncarcinogenic substances which employs starting materials which are readily obtainable.
This invention accordingly provides a process for preparing [bis-(trifluoromethyl)-phenyl]-acetic acids, characterized in that an appropriate bromo- or iodo-bis-(trifluoromethyl)-benzene is reacted with a di-C1-C4-alkyl malonate in the presence of a deprotonating agent and a copper salt and the reaction product is, in basic medium, hydrolysed and decarboxylated.